Tyrosine phosphorylation provides a universal mechanism of signal transduction in response to extracellular cues that regulate proliferation and differentiation in normal cells. Uncontrolled tyrosine kinase activation is implicated in proliferation of cancerous cells and deficiencies of specific tyrosine kinases result in a number of pathological conditions such as developmental abnormalities or immuno-deficiencies. Little is known at present about how cellular tyrosine kinases are regulated. Genetic studies in C. elegans have identified the sli-l proto-oncogene product as a potential regulator of tyrosine kinase signaling.
Sli-1 is a member of the Cbl family of proto-oncogenes that includes c-Cbl, Cbl-b and the Drosophila gene D-Cbl. Recent studies report that Cbl, the 120 kDa protein product of the c-cbl proto-oncogene (first identified as part of a transforming gene of a murine retrovirus and whose expression is predominant in haematopoietic cells), consists of an amino-terminal transforming region, a zinc ring finger, multiple proline-rich stretches, and several potential phosphotyrosine-containing motifs.
Cbl is reportedly tyrosine-phosphorylated, at a fast rate, in response to stimulation of a variety of cell-surface receptors and upon integrin-mediated cell adhesion. Cbl becomes associated with a number of intracellular signalling molecules such as protein tyrosine kinases, phosphatidylinositol-3-kinase, Crk, 14-3-3 proteins, and other cytoskeletal and adaptor proteins through different protein-interacting modules (including Src Homology 2 and 3-i.e., SH2 and SH3-domains), leading to the formation of multimolecular signalling complexes. Cbl can be rendered into a transforming factor by engineering mutations into its amino acid sequence. Cbl and its transforming mutants have been reported to display both negative and positive regulatory activities in protein tyrosine kinase- and Ras-mediated signalling pathways. The N-terminal region of c-Cbl (c-Cbl-N) harbors a tyrosine kinase binding domain, which presumably plays a regulating role in c-Cbl's transforming capabilities.
There exists a need to identify agents that desirably influence a cell's growth, differentiating and proliferative characteristics, and to provide diagnostics, research tools and therapeutics relating to such novel agents.
These and other objects will be described in greater detail below.